Dihydro-benzothiadiazine-1, 1-dioxides



United States Patent 3,297,693 DIHYDRO-BENZQTHHADEAZINE-LI-DIGXEDESGeorge de Stevens and Lincoln Harvey Werner, Summit, NJ, assignors toCilia Corporation, New York, N.Y.,

a corporation of Delaware No Drawing. Filed May 29, 1963, Ser. No.284,007 The portion of the term of the patent subsequent to Dec. 29,1981, has been disclaimer! 11 Claims. (Cl. 260--243) This application isa continuation-in-part application of our application Serial No.791,045, filed February 4, 1959, now abandoned, which in turn is acontinuation-in-part of our application Serial No. 764,482, filedSeptember 29, 1958, now abandoned, which in turn is acontinuation-inpart of our application Serial No. 751,620, filed July29, 1958, now abandoned, which in turn is a continuation-inpart of ourapplication Serial No. 740,582, filed June 9, 1958, now abandoned, whichin turn is a continuation-inpart of our application Serial No. 727,242,filed April 9, 1958, now abandoned, which in turn is acontinuation-inpart of our application Serial No. 718,452, filed March3, 195 8, now abandoned.

The present invention concerns 3-0xy-lower alkyl-3,4-dihydro-2-H-[1,2,4]-benzothiadiazine-1,l-dioxides. More particularly, itrelates to compounds of the formula:

in which R represents a hydroxy-lower alkyl, acyloxylower alkyl oretherified hydroxy-lower alkyl, each of the radicals R R and R standsfor hydrogen or lower alkyl and R represents lower alkyl, halogeno-loweralkyl or halogen, or alkali metal salts thereof, as well as process forthe preparation of such compounds.

The lower alkyl portion in the oxy-lower alkyl substituent isrepresented primarily by a lower alkylene radical having from one toseven carbon atoms; such radicals are 1,1-methylene, l,1-ethylene,1,2-ethylene, 1,l-dimeth' yl-1,2-ethylene, 1,1-propylene, 1,2-propylene,1,3-propylene, 2,3-propylene, 2,2-propylene, 1,1-butylene, 1,2-butylene,1,3-butylene, l,4butylene, 2,2-butylene, 2,3-butylene, 1,5-pentylene,2,5-pentylene, etc.

The lower alkyl group may be substituted by free hydroxyl.

An acyloxy group represents primarily a hydroxyl group esterified by anorganic carboxylic acid, for example, a substituted carbonic acid, e.g.,methoXy-carbonic acid, ethoXy-carbonic acid or benzyloXy-carbonic acid,a lower aliphatic carboxylic acid, such as a lower alkanoic acid, e.g.,acetic, propionic, or pivalic acid, lower alkenoic acids, e.g., acrylicor methylacrylic acid, lower aliphatic dicarboxylic acids, e.g., oxalic,malonic, succinic, glutaric, adipic, maleic or fumaric acid, or theirhalfesters with lower alkanols, e.g., methanol or ethanol. Carbocyclicaryl-carboxylic acids are primarily monocyclic carbocyclicaryl-carboxylic acids, e.g., benzoic or substituted benzoic acids,carbocyclic aryl-lower aliphatic carboxylic acids are primarilymonocyclic carbocyclic aryl-lower alkyl carboxylic acids, e.g.,phenylacetic or dihydrocinnamic acid, which may contain additionalsubstituents in the aromatic portion, or monocyclic carbocyclicaryl-lower alkenyl carboxylic acids, e.g., cinnamic acid or substitutedcinnamic acids. substituents of aromatic portions are particularly loweralkyl, e.g., methyl, hydroxyl, lower alkoxy, e.g., methoxy, or halogen,e.g., chlorine or bromine.

, mamas Patented Jan. 10, 1967 An etherified hydroxy-lower alkyl groupis represented, for example, by aliphatic hydrocarbonoxy, such as loweralkoxy, e.g., methoxy, ethoxy, n-propyloXy, isopropyloxy, n-butyloxy,isobutyloxy or similar alkoxy groups, lower alkenyloxy, e.g., vinyloxy,allyloxy or analogous alkenyloxy groups, carbocyclic aryloxy, such asmonocyclic carbocyclic aryloxy, e.g., phenyloxy or substitutedphenyloXy, or bicyclic carbocyclic aryloxy, e.g., l-naphthyloxy orZ-naphthyloxy or substituted naphthyloxy, or carbocyclic aryl-aliphatichydrocarbonoxy, such as monocyclic carbocyclic aryl-loweralkoxy, e.g.,benzyloxy or substituted benzyloxy. The aliphatic hydrocarbon, andparticularly the carbocyclic aryl portions of the etherified hydroxylgroups may contain additional substituents; such substituents have beenpreviously described as being present in the acyl portions of acyloxygroups.

The radicals R R and R represent primarily hydrogen; possible loweralkyl substituents are primarily methyl or ethyl.

The substituent R in the 6-position of the 3,4-dihydro-2-H-[l,2,4]-benzothiadiazine-1,l-dioxides of this invention representsprimarily halogen, such as fluorine, bro mine, or particularly chlorine.Furthermore, lower alkyl, e.g., methyl, or, more desirable,halogeno-lower alkyl, e.g., trifluoromethyl, may also be included assubstituents of the 6-position.

An alkali metal salt is particularly a sodium or a potassium salt.

The 3-0xy-loweralkyl-3,4-dihydro-2-H-[1,2,4]-bouzothiadiazine-1,1-dioxides of thisinvention have diuretic and natriuretic properties and can be used asdiuretic and natriuretic agents having improved properties to relieveexcessive states of water and sodium retention, as connected, forexample, with heart troubles. In addition, these compounds haveantihypertensive properties, which can be utilized to counteracthypertensive conditions.

Particularly useful as diuretic and natriuretic agents are the 2-R-3-acyloXy-lower alkyl-4-R "-6-R -7-(N- R "-sulfamyl)-3,4-dihydro-2 H[1,2,4]-benzothiadiazine-1,1-dioxides, in which each of the radicals R Rand R represents hydrogen or methyl, and R stands for methyl,trifluoromethyl, bromine or chlorine, and in which the acyl group isderived from a lower alkanoic acid, a monocyclic carbocyclicaryl-carboxylic acid or a monocyclic carbocyclic aryl-lower alkanoicacid. This group is represented by 2-R '-3lower alkanoyloxy-loweralkyl-6-R -7-sulfamyl-3,4-dihydr0-2-H-[1,2,4]benzothiadiazine-l,1-dioxides, in which R represents hydrogen or methyl,and R stands for chlorine or trifluoromethyl.

Another series of compounds of outstanding diuretic and natriureticeffects are the 2-R -3-etherified hydroxy lower alkyl-4-R -6-R -7-(N-R"-sulfamyl)-3,4-dihydro- 2-H-[1,2,4]-benzothiadiazine-1,1-dioxides, inwhich each of the radicals R R and R represents hydrogen or methyl, andR stands for methyl, trifiuoromethyl, bromine or chlorine, and in whichthe etherified hydroxyl group is represented by lower alkoxy, monocycliccarbocyclic aryloxy or monocyclic carbocyclic aryl-lower alkoxy. Thisgroup is represented by 2-R -3-l0wer alkoxylower alkyl-6-R-7-sulfamyl-3,4-dihydro-2-H-[1,2,4]-hen zothiadiazine-l,l-dioxides or2-R 3-monocyclic carbocyclic aryloxy-lower alkyl-6 R7-sulfamyl-3,4-dihydro-2- H-[1,2,4]-benzothiadiazine-1,l-dioxides, inwhich R represents hydrogen or methyl and R stands for chlorine ortrifiuoromethyl.

The new compounds of this invention may be used as medicaments in theform of pharmaceutical preparations, which contain the new3,4-dihydro-2-H-[1,2,4]benzothiadiazine-1,1-dioxides or the saltsthereof in admixture with a pharmaceutical organic or inorganic, solidor liquid carrier suitable for enteral, eg. oral, or parenteraladministration. For making up the preparations there can be employedsubstances which do not react with the new compounds, such as water,gelatine, lactose, starches, stearic acid, magnesium stearate, stearylalcohol, talc, ve etable oils, benzyl alcohols, gums, waxes, propyleneglycol, polyalkylene glycols or any other known carrier for medicaments.The pharmaceutical preparations may be in solid form, for example, ascapsules, tablets or dragees, or in liquid form, for example, assolutions, suspensions or emulsions. If desired, they may containauxiliary substances such as preserving agents, stabilizing agents,wetting or emulsifying agents, salts for varying the osmotic pressure orbuffers. They may also contain, in combination, other therapeuticallyuseful substances.

'The compounds of this invention are advantageously prepared by reactingan aniline compound of the formula:

in which R R R and R have the previously given meaning, with an aldehydeof the formula R CHO, in which R has the above-given meaning, or aderivative thereof, and, if desired, replacing in a resulting3,4-dihydro-2-I-I-[1,2,4]-benzothiadiaziue-1,1-dioxide containing asulfamyl-nitrogen with hydrogen, such hydrogen by lower alkyl, and/or,if desired, hydrolyzing in a resulting 3-acyloxy-loweralkyl-3,4-dihydro-2-H-[1,2,41-benzothiadiazine-1,l-dioxide the acyloxygroup to a hydroxyl group, and/or, if desired, converting a resultingsalt into the free compound, and/or, if desired, converting a resultingfree compound into a salt thereof.

Although the aldehyde is preferably reacted with the aniline derivativein approximately stoichiometric amounts, it may also be given to thereaction mixture in excess amounts. The reaction may be performed in theabsence of any condensing reagent, or in the presence of a base, such asan alkali metal hydroxide, e.g., lithium, sodium or potassium hydroxide,whereby the aldehyde is used in its reactive form. It may also becarried out in the presence of a small amount of an acid, for example, amineral acid, such as hydrohalic acid, eg, hydrochloric or hydrobromicacid, or sulfuric acid, if desired, in anhydrous form. Furthermore, thealdehyde may be given into the reaction medium in a form which yieldsthe desired reactant in situ. Thus, for example, an acetal of analdehyde R -CHO with a lower alkanol, for example, methanol or ethanol,may be used, whereby the presence of an acid is necessary to convert thederivative, e.g., the acetal, into the reactive form. Such acetals are,for example, 1,1-dimethoxy-Z-methoxy-ethane, 1,1-diethoxy-2-ethoxy-ethane, 1,l-diethoxy-2-phenoxy-ethane, etc.

The reaction may be carried out in the absence or preferably in thepresence of a solvent, for example, an ether, e.g., p-dioxane ordiethyleneglycol dimethylether, a lower alkanol, e.g., methanol orethanol, or a formamide, e.g., dimethylformamide, or an aqueous mixtureof such solvents or water. If desired, it may be completed at anelevated temperature, for example, on the steam bath or at the boilingtemperature of the solvent. If necessary, the reaction may be performedunder increased pressure or in the atmosphere of an inert gas, e.g.,nitrogen.

The starting materials used in the above-described reactions are known,or, if new, may be prepared according to procedures used for themanufacture of known compounds. For example, by treatment of a 3-R -N-Raniline, in which R and R have the above-given meaning, withchlorosulfonic acid, two sulfonyl chloride groups are introduced to form3-R -N-R -aniline-2,4-disulfonyl chlorides. These are subsequentlyreacted with ammonia, e.g., liquid or gaseous ammonia or a solution ofammonia in water or in a lower alkanol, methanol or ethanol, or with alower alkylamine, e.g., methylamine or ethylamine,

to yield the desired starting materials of the above-mentioned type. Thesulfamyl groups of the starting material may also be introduced instages; for example, one of the sulfonyl chloride groups may beconverted to a sulfamyl group with ammonia or a lower alkylamine bycontrolling the reaction as to amounts of the reactants and/or thereaction conditions, and the second sulfonyl chloride group may then beconverted to the desired sulfamyl group.

A second procedure to prepare the compounds of this invention comprisesreducing in compounds of the formulae:

in which R R R and R have the previously given meaning, the C=Ndoublebond of the 1,2,4-thiadiazine- 1,1-dioxide portion, and, if desired,replacing in any resulting3,4-dihydro-2-H-[1,2,4]-benzothiadiazine-1,l-dioxide containingsulfamyl-nitrogens with hydrogen, such hydrogen by lower alkyl, and/or,hydrolyzing in a resulting 3-acyloxy-loweralkyl-3,4-dihydro-2-H-[1,2,4]-benzothiadiaZine-1,l-dioxide the acyloxygroup to a hydroxyl group, and/or, if desired, converting a resultingsalt into a free compound, and/or, if desired, converting a freecompound into a salt thereof.

The removal of the C=Ndouble bond may be achieved, for example, bytreatment with a borohydride or an equivalent reducing agent capable ofreducing such bond. The preferred reagents are alkali metalborohydrides, e.g., lithium borohydride, potassium borohydride or,particularly sodium borohydride. Other borohydrides are alkaline earthmetal borohydrides such as calcium or strontium borohydride; aluminumborohydride may be used as well. Sodium dimethoxy borohydride is anotherpossible reagent to be used in the reaction. If desired, theseborohydrides may be used in the presence of an activating substance,such as, for example, aluminum chloride. The reaction may also becarried out in the presence of an alkaline reagent, such as an aqueousalkaline reagent, which may be diluted with other sol vents, such asthose mentioned hereinbelow; such alkaline reagents are, for example,dilute aqueous solutions of alkali metal hydroxide, e.g., lithium,sodium or potassium hydroxide. If desired, organic solvents, such asethers, e.g., 1,2-dimethoxy-ethane or diethyleneglycol dimethylether;lower alkanols, e.g., methanol, ethanol, propanol, or isopropanol; orliquid carboxylic acid amides, such as formamides, e.g., formamide ordimethylformamide, may be employed. The reduction is carried out at roomtemperature or at an elevated temperature, if necessary, in theatmosphere of an inert gas such as nitrogen.

The electrolytic reduction procedure provides for another possibility ofremoving the C=Ndouble bond; such procedure is carried out according tostandard methods. Generally, it is performed on a cathode of highoverpotential and at a current density greater than about 0.02 amp./cm.Cathodes with high overpotentials are, for example, those having anoverpotential equal to or higher than cadmium, such as cadmium, zinc,mercury, lead amalgam or lead. Any appropriate anode, such as platinum,carbon, lead or stainless steel, and any appropriate anolyte, forexample, dilute sulfuric acid or dilute hydrochloric acid, may beemployed. A lead or platinum anode and a dilute sulfuric acid anolyteare preferred.

Any current density greater than about 0.02 amp./ cm. is sufficient tobring about the reduction of the G N-double bond; however, for practicalreasons a current density higher than about 0.25 amp/cm. may diminishthe efiiciency of the process due to increased hydrogen evolution.

The reduction is performed in an aqueous acidic medium, such as, forexample, an aqueous solution of a strong inorganic acid, which ionizesreadily and does not decompose at the current density employed, such asfor example, sulfuric acid. In order to secure a complete solution ofthe starting material an additional solvent, such as, for example, aformamide, e.g., N,N-dimethylformamide, may be added. Lower alkanols,e.g., methanol or ethanol, may replace or may be added with a formamideto enhance the solubility of the starting material and the end product.

Diaphragms separating the .anlyte and the catholyte are more especiallyion exchange membranes, such as ion exchange resins (Amberplex),Alundurn or parchment.

Any groups, which may be affected by the hydrogenation procedure, may beprotected or simultaneously converted into hydrogenated groups.

The starting materials used in this reaction are known, or, if new, maybe obtained according to procedures used for the preparation of theknown compounds.

In resulting 3-oxy-lower alkyl-3,4-dihydro-2-H-[1,2,4]-benzothiadiazine-1, l-dioxides, containing sulfamyl-nitrogens withhydrogen, such hydrogen may be replaced by lower alkyl. Generally, analkali metal salt of the starting material is formed and such salt isthen reacted with the reactive ester of a lower alkanol. These estersare particularly those of lower alkanols, e.g., ethanol, or particularlymethanol, with strong mineral acids, such as hydrohalic acids, e.g.,hydrochloric, hydrobromic or bydriodic acid, or sulfuric acid. Forexample, treatment of the starting material with a di-lower .alkylsulfate, such as, for example, dimethyl sulfate or diethyl sulfate, inthe presence of an alkaline reagent, such as an alkali metal hydroxide,e.g., lithium, sodium or potassium hydroxide, is a preferred procedure.As solvents water or water miscible organic solvents, such as loweralkanols, e.g., methanol, ethanol, propanol, isopropanol or tertiarybutanol; ethers, e.g., diethyleneglycol dimethylether, or formamides,e.g., dimethylformamide, may be used.

Generally, the alkylation reaction may be carried out under cooling, atroom temperature, or at an elevated temperature, if necessary, in aclosed vessel, e.g., sealed tube, under pressure and/or in theatmosphere of an inert gas, e.g., nitrogen.

An N-unsubstituted sulfamyl group in the carbocyclic portion of themolecule may simultaneously be alkylated; if necessary, this may beprevented to a large extent by varying the conditions and/or the molarratios of the reactants. A resulting mixture of products may beseparated into the single components, for example, by fractionatedcrystallization, utilizing the differing solubilities in differentsolvent systems.

The resulting product may be obtained in the form of the free compoundor as a salt thereof. An alkali metal salt may be converted into thefree compound by treatment with an aqueous acidic reagent, such as amineral acid, for example, hydrohalic acid, e.g., hydrochloric acid, orsulfuric acid. A free compound may be converted into an alkali metalsalt, for example, by treatment with an alkali metal hydroxide, e.g.,sodium or potassium hydroxide, in a solvent, such as in a lower alkanol,e.g., methanol or ethanol, or in water and evaporating the solvent; orby reacting the free compound, for example, in an ether, e.g., p-dioxaneor diethyleneglycol dimethylether, solution, with an alkali metalhydride or amide, e.g., sodium or potassium hydride or amide, andremoving the solvent. Monoor polysalts may be obtained.

Any resulting racemate may be converted into the antipodes thereofaccording to methods used for resolving racernates.

The following examples illustrate the invention; they are not to beconstrued as being limitations thereon. Temperatures are given indegrees centigrade.

Example 1 To a solution of 5.8 g. of 5-chloro-2,4-disulfamylaniline in30 ml. of diethyleneglycol dimethylether are added 1 ml. of a 2Nsolution of hydrogen chloride in anhydrous ethyl acetate and 4.2 g. ofphenoxy-acetaldehyde diethylacetal, and the reaction mixture is heatedto -90 for one hour. The solvents are removed under reduced pressure,the residue is triturated with hexane and on addi tion of-water acrystalline material is formed. The 6-chloro-3-phenoxymethyl-7-sulfamyl-3,4 dihydr-o 2 H- [l,2,4]-benzothiadiazine 1,1 dioxide is recrystallized from aqueousdimethyl-formamide, M.P 262264; yield: 6.5 g.

.Upon treatment of a solution of the 6-chloro-3-phenoxymethyl 7sulfamyl-3,4-dihydro-2-H-[1,2,4] benzothiadiazine-1,1-dioxide in aqueoussodium hydroxide with dimethyl sulfate at 10 for one hour and a roomtemperature for an additional hour, the 6-chloro-2-methyl-3-phenoxymethyl 7 sulfamyl-3,4-dihydro-2-H-[1,2,4]-benzothiadiazine-1,l-dioxide can be prepared and may beseparated from any simultaneously formed 6-chloro-2-methyl-3-phenoxymethyl 7 (N methylsulfamyl)-3,4-dihydro-2-T-[1,2,4] benzothiadiazine 1,1- dioxide byfractionated crystallization.

A sodium salt may be prepared by evaporating a solution of the6-chloro-3-phenoxymethyl-7-sulfa'myl-3,4-dihydro-2-H-[1,2,4]-benzothiadiazine-1,1-dioxidein a stoichiometric amount of aqueous sodium hydroxide.

Instead of 5-chloro-2,4-disulfamyl-aniline, 2,4-disulfamyl-S-methylaniline or 2,4 disulfamyl-S-trifiuoromethyl-aniline may be reacted withthe diethylacetal of phenoxy-acetaldehyde to yield6-methyl-3-phenoxymethyl- 7-sulfamyl-3,4-dihydro-2-H- [1,2,4]benzothiadiazine-l ,1- dioxide and 3 phenoxymethyl-7-sulfarnyl 6trifluoromethyl-3,4-dihydro-2-H-[1,2,4] benzothiadiaz ine-Lbdioxide,respectively.

Example 2 To a solution of 1.2 g. of 3-acetoxymethyl-6-chloro-7-sulfamyl-[1,2,4]-benzothiadiazine-1,1-dioxide in 30 ml. ofdiethyleneglycol dimethylether is added 0.3 g. of sodium borohydride.The reaction mixture is allowed to stand at room temperature for 1 /2hours and is then concentrated under reduced pressure. Water is added tothe residue and the solution is neutralized with diluted aqueoushydrochloric acid. The solvent is removed under reduced pressure, wateris added and the solid material is filtered off; the3-acetoxymethyl-6-chlOro-7-sulfamyl-3,4-dihydro-2-H-[1,2,4]-benzothiadiazine 1,1 dioxide is recrystallized twice fromaqueous dimethylformamide, M.P. 264- 265; yield: 0.3 g.

The starting material is prepared by reacting5-chloroaniline-2,4-disulfamyl chloride with acetoxy-glycolic acidchloride, followed by treatment with ammonia to yield the desired3-acetoxymethyl-6-chloro-7-sulfamy1-[1,2,4]-benzothiadiazine-l,l-dioxide, M.P. 310-3 12.

Example 3 Toa solution of 5.9 g. of 5-chloro-2,4-disulfamyl-aniline in30 ml. of diethyleneglycol dimethylether are added 1 ml. of a 2Nsolution of hydrogen chloride in ethyl acetate and 3.2 g. ofethoxy-acetaldehyde diethylacetal and the mixture is heated to 8090 forone hour and then cooled. Upon concentration under reduced pressure andaddition of water an oily product is formed; the water is decanted andon addition of ether a crystalline material precipitates, which isfiltered off. The6-chloro-3-ethoxymethyl-7-sulfamyl-3,4-dihydro-2-H-[1,2,4]benzothiadiazine 1,1-dioxide is recrystallized three times from a 1:1-mixture of ethanol and water, M.P. 186'190; yield: 2.4 g.

By substituting in the above reaction methoxy-acetaldehyde diethylacetalor 3-ethoxy-propionaldehyde dimethylacetal for the ethox-y-acetaldehydediethylacetal, the 6- chloro-3-methoxymethyl 7 sulfamyl-3,4 dihydro-2-H-[1,2,41-benzothiadiazine 1,1-dioxide and 6-chloro-3-(2-ethoxyethyl)-7-sulfamyl 3,4dihydro-2-H-[l,2,4]-benzothiadiazine-l,l-dioxide, respectively, can beobtained.

Example 4 A mixture of -chloro-2,4-disulfamyl-aniline,benzylox-yacetaldehyde diethylacetal, a small amount of a sat-uratedsolution of hydrogen chloride in ethyl acetate and diethyleneglycoldimethylether, when treated as described in Example 3, yields the3-benzyloxymethyl-6-chloro-7- sulfamyl3,4-dihydro-2-H-[1,2,4]-benzothiadiazine-l,1- dioxide, purified byrecrystallization from aqueuos ethanol.

In place of benzyloxy-acetaldehyde diethyl-acetal substitutedbenzyloxy-acetaldehyde acetals, such as, for example,4-methoxy-benzyloxy-acetaldehyde dimethylacetal, 4-chloro benzyloxyacetaldehyde diethylacetal or 3- methyl-benzyloxy-acetaldehydediethylacetal, may be reacted with 5-ch1oro-2,4-disulfamyl-aniline toyield 6- chloro-3-(4-methoxy benzyloxymethyl)-7-sulfamyl-3,4-dihydro-2-H-[1,2,4]-benzothiadiazine 1,1 dioxide, 6- chloro-3-(4-chlorobenzyloxymethyl)-7-sulfamyl 3,4- dihydro-2-H-[1,2,4]-benzothiadiazine1,1 -dioxide and 6- chloro-3-(3-methylbenzyloxymethyl)-7-sulfamyl-3,4-dihydro-2-H-[1,2,4]-benz0thiadiazine 1,1dioxide, respectively.

Example 5 5.9 g. of 4-amino-6-chloro-1,3-benzenedisulfonamide isdissolved in 30 ml. of diglyme'and 0.5 ml. of 3N hydrochloric acid inethyl acetate and 2.04 g. of fl-ethoxy propionaldehyde are added. Thereaction mixture is heated for 1 hour to 8090, then concentrated invacuo. The residue is tr iturated with 30 ml. of water, followed bytrituration with 30 ml. of hexane. The crude product is filtered off anddissolved in 2N sodium hydroxide and precipitated by acidifying with 2Nhydrochloric acid. The product is then dissolved in ethyl acetate; onaddition of hexane the pure 6-chloro-3-(2-ethoxyethyl)-3,4-dihydro-7-sulfamyl 1,2,4 benzothiadiazine-l,l-dioxide separates (meltingpoint 224 C. with decomposition).

Example 6 By using 5.9 g. of 4-amino-6-chloro-1,3-benzenedisulfonamideand 2.5 g. of 2-al1yloxy proprionaldehyde and following the procedure ofExample 5, 3 (2 allyloxyethyl)-6-chloro-3,4-dihydro-7-sulfamyl-1,2,4benzothiadiazine-1,1-dioxide is obtained.

Example 7 A mixture of 114 g. of cyclohexanemethanol and 14 g. ofacrolein containing 0.7 g. of catalyst (diethylamine and formic acid ina molar ratio of 1:1.75) is heated to 90100 for 14 hours, thenfractionated by distillation to give3-(cyclohexylmethoxy)-propionaldehyde.

5.9 g. of 4-amino-6-chloro-1,3-benezenedisulfonamide is dissolved in 30ml. of diglyme and 3.5 g. of 3-(cyclohexylmethoxy)-propionaldehyde, and0.5 ml. of approximately 3N hydrochloric acid in ethyl acetate is added.The reaction mixture is heated for 1 hour to 90, then concentrated invacuo. The residue is first triturated with water, then with ether. Ontreatment with aqueous alcohol (1:1) the 6-chloro-3-(2-cyclohexylmethoxyethyl)-3,4 dihydro-7 sulfamyl 1,2,4-benzothiadiazine-1,1-dioxidecrystallizes.

8 Example 8 5.9 g. of 4-amino-6-chloro-1,3-benzenedisulfonamide isdissolved in 30 ml. of diglyme and 3.6 g. of 3-benzoyloxypropionaldehydeand 0.5 ml. of approximately 3N hydrochloric acid in ethyl acetate isadded. The reaction mixture is heated on a steam bath to 90 for 1 hour,then concentrated in vacuo. The residue is triturated with Water, thenwith hexane. On treatment with aqueous alcohol (1:1) the residue slowlycrystallizes to give 3-(2-benzoyloxyethyl)-6-ohloro-3,4-dihydro-7sulfamyl- 1,2,4-benzothiadiazine-1,1-dioxide.

Example 9 5.9 g. of 4-amino-6-chloro-1,3-benzenedisulfonamide isdissolved in 30 ml. of dimethyl formamide and 3.6 g. of3-benzoyloxypropionaldehyde and 2.3 g. of anhydrous potassium fluorideis added. The reaction mixture is heated on a steam bath to 8090 for twohours, then the potassium fluoride is filtered off and the filtrateconcentrated in vacuo. The residue is triturated with water, then withhexane. On treatment with aqueous alcohol (1:1) the residue slowlycrystallizes to give 3-(2-benzoyloxyethyl)-6-chloro-3,4 dihydro 7sulfamyl 1,2,4- benzothiadiazine-l,l-dioxide.

In resulting 3,4-dihydro-2-H-[1,2,4]-benzothiadiazine- 1,1-dioxidescertain substituents may be converted to other sulbstituents; forexample, the 3-acetoxymethyl-6- chloro-7-sulfamyl 3,4 dihydro-Z-H[1,2,4] benzothiadiazine-1,1-dioxide may be hydrolyzed to the 6-chloro-3-hydroxymethyl-7-sulfamyl 3,4 dihydro 2-H-[1,2,4]-benzothiadiazine-1,1-dioxide by treatment with an alkalinereagent, such as aqueous alkali metal hydroxide, e.g., sodium orpotassium hydroxide.

The replacement in 3-acyloxy-lower alkyl-3,4-dihydro-2-H-[1,2,4]-benzothiadiazine-1,l-dioxides with sulfamylnitrogen atomscontaining hydrogens, of such hydrogens by lower alkyl, should becarried out in the absence of a hydrolyzing reagent unless asimultaneous hydrolysis of the acyloxy group is desired; the alkalimetal salt is, therefore, formed under anhydrous conditions and a loweralkyl halide, e.g., methyl or ethyl chloride, bromide or iodide, may beused as an alkylating reagent, preferably in a sealed tube and at anelevated temperature.

What is claimed is:

1. A member of the group consisting of 3,4-dihydro-2-H-[1,2,4]-benzothiadiazine-1,l-dioxides of the formula:

in which R represents a member of the group consisting of hydroxy-loweralkyl, lower alkanoyloxy-lower alkyl, lower alkoxy-carbonyloxy-loweralkyl, benzyloxycarbonyloxy-lower alkyl, carboxy-lower alkanoyloxyloweralkyl, monocyclic carbocyclic aryl-lower alkanoyloxy-lower alkyl, loweralkoxy-lower alkyl, lower alkenyloxy-lower alkyl, monocyclic carbocyclicaryloxy-lower alkyl and monocyclic carbocyclic aryl-lower alkoxyloweralkyl, each of the radicals R R and R represents a member of the groupconsisting of hydrogen and lower alkyl, and R stands for a member of thegroup consisting of lower alkyl, halogeno-lower alkyl and halogen, andalkali metal salts thereof.

2. 3-Lower alkoxy-lower alkyl-6-halogeno-7-sulfamyl-3,4-dihydro-2-H-[1,2,4]-benzothiadiazine-1,l-dioxide.

3. 3-Methoxymethyl-6-chloro-7-sulfarnyl-3,4 dihydro-2-H-[1,2,4]-benzothiadiazine-1,l-dioxide.

4. 6-Chloro-3-ethoxymethyl 7- sulfamyl-3,4-dihydro-2-H-[1,2,4]-benzothiadiazine-1,1-dioxide.

5. 6-Halogeno-3-monocyclic carbocyclic aryloxy-lower

1. A MEMBER OF THE GROUP CONSISTING OF3,4-DIHYDRO-2H-(1,2,4)-BENZOTHIADIAZINE-1,1-DIOXIDES OF THE FORMULA: